In U.S. Pat. No. 3,159,617, there is taught the first commercial syntheses of 6.beta.-aminopenicillanic acid and penicillin derivatives based thereon. A vast number of derivatives of the 6.beta.-aminopenicillanic acid may be formed by introduction of various groups into the amino group of the acid. Thus, acyl groups, isocyanates, isothiocyanates, halogen compounds, methylisoureas, ethylene oxide, ethylene imine, and the like have been introduced into the amino group of 6.beta.-aminopenicillanic acid to form both biologically active and biologically inactive derivatives.
Many of the derivatives of 6.beta.-aminopenicillanic acid, especially those derivatives formed by acylation, have become useful drugs. For example, ampicillin and carbenicillin have broadened the spectra to activity to include use against certain Gram-negative organisms while methicillin shows good activity against certain resistant staphylococci.
In an effort to find new biologically active derivatives of 6.beta.-aminopenicillanic acid, attempts have been made to modify the parent compounds by myriad methods, in addition to the mere functionalization of the amino group. Thus, stimulated by the eluciadation of the structure of the cephalosporins, there have been attempted modifications of the thiazolidine moiety of 6.beta.-aminopenicillanic acid. This transformation is particularly useful since cephalosporins are not readily available from nature. Thus, much effort has been concentrated on the investigation of possible transformations of the thiazolidine ring to the dihydrothiazine ring without any concomitant change of the chemically sensitive .beta.-lactam moiety. These efforts are described by D. H. R. Barton and T. G. Sammes, Proc. R. Soc. Lond. B, 179 345 (1971).
Other attempts have been made to modify 6.beta.-aminopenicillanic acid through reaction of the .beta.-lactam moiety, but such attempts are relatively few and are focused on variation of the substituents or sterochemistry of the C-6 carbon in the penam system. Primarily, four types of modifying reactions are reported, namely acylation, epimerization, alkylation and diazotization.
One successful example of the epimerization reaction is reported by G. E. Gutowski, Tet. Lett., (1970), 1779 and 1863. However, this penicillin having the epimerized C-6 substituent is devoid of any biological activity. With regard to alkylation at the C-6 position, most attempts, based upon earlier predictions that the introduction of an .alpha.-methyl group at the C-6 position might enhance antibiotic activity, have been directed to such introduction. Further, both direct and indirect .alpha.-hydroxylalkylation of the penicillin nucleus at C-6 with benzaldehyde and formaldehyde has been reported by R. Riner and P. Zeller, Helv Chim. Acta, 51, 1905 (1968). These derivatives and other .alpha.-alkylated derivatives show some biological activity, but both display substantially less activity than the well known penicillin G.
Deamination of .beta.-aminopenicillanic acid by sodium nitrite in mineral acid proceeds with inversion at C-6, resulting in the C-5 and C-6 protons being trans-oriented in the product. Moreover, when the reaction is run in the presence of a haloacid, a 6.alpha.-halo product is obtained. Deamination of 6.beta.-aminopenicillanic acid by sodium nitrite with oxy acids is reported by T. Hauser and H. P. Sigg, Helv. Chim Acta, 50, 1327, (1967). With such oxy acids, 6.alpha.-hydroxypenicillanic acid is isolated as the benzyl ester and is readily transformed to the .alpha.-oxygen analog of penicillin V, 6.alpha.-phenoxyacetoxypenicillanic acid. This material also exhibits no biological activity.
Similar chemical transformations and derivatizations in the cephalosporin antibiotic series are reported in part by R. B. Morin and B. G. Jackson, "Chemistry of Cephalosporin Antibiotics", Progress in the Chemistry of Organic Natural Products XXVIII, Wein, Springer-Verlag (1970).
A naturally occurring cephalosporanic derivative containing an .alpha.-methoxy group in the 7- position was isolated from Streptomyces lipmanii NRRL 3584 and reported by Higgens and Kastner, (1971) and by Nagarajan et al., (1971) to have exhibited greater activity than Cephalosporin C against gram-negative microorganisms (See Edwin H. Flynn, "Cephalosporins and Penicillins: Chemistry and Biology", Chapter 15, Academic Press, New York and London (1972). Cama et al. describe the stereospecific introduction of a methoxy group at the C-6(7) position of derivatives of naturally occurring penicillin and cephalosporin compounds in "Substituted Penicillin and Cephalosporin Derivatives. I. Stereospecific Introduction of the C-6(7) Methoxy Group", J. Amer. Chem. Soc., 94 1408 (1972).
Further, three new series of these penicillins and cephalosporins have recently been described in copending U.S. Patent Appln. Ser. No. 347,772, filed Apr. 3, 1973; U.S. Patent Appln. Ser. No. 494,507, filed Aug. 5, 1974; U.S. Patent Appln. Ser. No. 616,979, filed Sept. 26, 1975; and U.S. Patent Appln. Ser. No. 712,540, filed Aug. 9, 1976. These series, the carbon, oxygen and sulfur analogs of penicillins and cephalosporins, are characterized by the replacement of the 6-nitrogen of the "normal" antibiotic with carbon, oxygen or sulfur, respectively. These novel analogs and the wide variety of derivatives obtainable therefrom are biologically active and provide new series of antibiotics.
For brevity, the commonly accepted abbreviations of 6-APA for 6.beta.-aminopenicillanic acid, 6-SPA for the sulfur analogs thereof, 7-ACA for 7.beta.-aminocephalosporanic acid and 7-SCA for the sulfur analogs thereof will be used throughout the specification.